Large substitutent, non-phenolic opioids and methods of use thereof

ABSTRACT

8-Substituted-2,6-methano-3-benzazocines of general structure 
     
       
         
         
             
             
         
       
     
     are useful as analgesics, anti-diarrheal agents, anticonvulsants, antitussives and anti-addiction medications.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional of allowed U.S. application Ser. No.14/529,832, filed Oct. 31, 2014; which is a divisional of U.S.application Ser. No. 13/974,216, filed Aug. 23, 2013, and issued as U.S.Pat. No. 8,901,148 on Dec. 2, 2014; which is a divisional of U.S.application Ser. No. 13/215,392, filed Aug. 23, 2011, and issued as U.S.Pat. No. 8,541,586 on Sep. 24, 2013; which is a continuation of U.S.application Ser. No. 12/477,223, filed Jun. 3, 2009, and issued as U.S.Pat. No. 8,026,252 on Sep. 27, 2011; which is a continuation of U.S.application Ser. No. 11/459,203, filed Jul. 21, 2006, and issued as U.S.Pat. No. 7,557,119 on Jul. 7, 2009; and claims priority of U.S.provisional application 60/701,407, filed Jul. 21, 2005. The entiredisclosures of each of the prior applications are hereby incorporatedherein by reference.

FEDERALLY SPONSORED RESEARCH

The following invention was made with Government support under contractnumber 5 R₀₁ DA12180 awarded by U.S. Dept of Health and Human Services.The Government has certain rights in this invention.

FIELD OF THE INVENTION

The invention relates to opioid receptor binding compounds containingcarboxamides that have large substitutents on the nitrogen of thecarboxamide. The compounds are useful as analgesics, anti-diarrhealagents, anticonvulsants, anti-obesity agents, antitussives,anti-cocaine, and anti-addiction medications.

BACKGROUND OF THE INVENTION

Opiates have been the subject of intense research since the isolation ofmorphine in 1805, and thousands of compounds having opiate oropiate-like activity have been identified. Many opioidreceptor-interactive compounds including those used for producinganalgesia (e.g., morphine) and those used for treating drug addiction(e.g., naltrexone and cyclazocine) in humans have limited utility due topoor oral bioavailability and a very rapid clearance rate from the body.This has been shown in many instances to be due to the presence of the8-hydroxyl group (OH) of 2,6-methano-3-benzazocines, also known asbenzomorphans [(e.g., cyclazocine and EKC (ethylketocyclazocine)] andthe corresponding 3-OH group in morphinanes (e.g., morphine).

The high polarity of these hydroxyl groups retards oral absorption ofthe parent molecules. Furthermore, the 8-(or 3-)OH group is prone tosulfonation and glucuronidation (Phase II metabolism), both of whichfacilitate rapid excretion of the active compounds, leading todisadvantageously short half-lives for the active compounds. Until thepublications of Wentland in 2001, the uniform experience in the art ofthe past seventy years had been that removal or replacement of the 8-(or3-) OH group had led to pharmacologically inactive compounds.

U.S. Pat. No. 6,784,187 (to Wentland) disclosed that the phenolic OH ofopioids could be replaced by CONH2. In the cyclazocine series ofopioids, it was shown that 8-carboxamidocyclazocine (8-CAC) had highaffinity for μ and κ opioid receptors. In studies in vivo, 8-CAC showedhigh antinociception activity and a much longer duration of action thancyclazocine (15 h vs. 2 h) when both were dosed at 1 mg/kg ip in mice.Preliminary structure-activity relationship studies for 8-CAC revealedthat mono-substitution of the carboxamide nitrogen with methyl or phenylreduced binding affinity for guinea pig μ receptors 75- and 2313-fold,respectively whereas dimethylation of the carboxamide group reducedbinding affinity 9375-fold. The finding that substitution of thecarboxamide nitrogen had such a detrimental effect suggested that theNH2 of the amide was critical to opioid binding.

SUMMARY OF THE INVENTION

We have now found that the nitrogen of the carboxamide can besubstituted with fairly large and relatively non-polar groups, and thatsuch compounds exhibit excellent opioid binding and, presumably, goodmetabolic stability. The compounds of the invention are therefore usefulas analgesics, anti-pruritics, anti-diarrheal agents, anticonvulsants,antitussives, anorexics and as treatments for hyperalgesia, drugaddiction, respiratory depression, dyskinesia, pain (includingneuropathic pain), irritable bowel syndrome and gastrointestinalmotility disorders. Drug addiction, as used herein, includes alcohol andnicotine addiction. There is evidence in the literature that thecompounds may also be useful as immunosuppressants andantiinflammatories and for reducing ischemic damage (andcardioprotection), for improving learning and memory, and for treatingurinary incontinence.

In one aspect, the invention relates to compounds of formula:

wherein

is an aryl or heteroaryl residue of one to three rings;

A is (CH₂)_(n), wherein one or more CH₂ may be replaced by —O—,cycloalkyl or —CR^(1a)R^(1b);

R^(1a) and R^(1b) are chosen independently from hydrogen, halogen, loweralkyl, lower alkoxy and lower alkylthio;

R² and R^(2a) are both hydrogen or taken together R² and R^(2a) are ═O;

R³ is chosen from hydrogen, C₁-C₈ hydrocarbon, heterocyclyl,heterocyclylalkyl and hydroxyalkyl;

R⁴ is chosen from hydrogen, hydroxy, amino, lower alkoxy, C₁-C₂₀ alkyland C₁-C₂₀ alkyl substituted with hydroxy or carbonyl;

R⁵ is lower alkyl;

R⁶ is lower alkyl;

R⁷ is chosen from hydrogen and hydroxy; or

together R⁴, R⁵, R⁶ and R⁷ may form from one to three rings, said ringshaving optional additional substitution;

R¹⁰ is one or two residues chosen independently from hydrogen, hydroxyl,halogen, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, halo(C₁-C₆)alkyl andhalo(C₁-C₆)alkoxy and (C₁-C₆)alkylthio;

R¹¹ is H or

is an aryl or heteroaryl residue of one to three rings;

A′ is (CH₂)_(m), wherein one or more CH₂ may be replaced by —O—,cycloalkyl, —CR^(1a)R^(1b), —C(═O)— or —NH—;

R¹² is chosen from hydrogen and lower alkyl;

R¹⁵ is one or two residues chosen independently from hydrogen, hydroxyl,halogen, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, halo(C₁-C₆)alkyl andhalo(C₁-C₆)alkoxy and (C₁-C₆)alkylthio;

m is zero or an integer from 1 to 6; and

n is an integer from 1 to 6.

Subclasses of the foregoing structure include:

II. 2,6-methano-3-benzazocines of the structure shown above, in whichR⁴, R⁵, R⁶ and R⁷ do not form additional rings:

wherein:

R^(3a) is chosen from hydrogen, C₁-C₇ hydrocarbon, heterocyclyl, andhydroxyalkyl;

R⁴ is chosen from hydrogen, hydroxy, lower alkoxy, C₁-C₂₀ alkyl andC₁-C₂₀ alkyl substituted with hydroxy or carbonyl;

R⁵ is lower alkyl;

R⁶ is lower alkyl; and

R⁷ is hydrogen or hydroxy.

III. morphinans in which R⁵ and R⁶ form one ring:

wherein

R^(3a) is chosen from hydrogen, C₁-C₇ hydrocarbon, heterocyclyl, andhydroxyalkyl; and R⁷ is H or OH.

IV. morphinans in which R⁵, R⁶ and R⁷ form two rings:

wherein

R¹⁹ is hydrogen or lower alkyl;

R₂₀ is chosen from hydrogen, lower alkyl and hydroxy(lower alkyl); ortogether, R⁹ and R¹⁰ form a spiro-fused carbocycle of 5 to 10 carbons;

R²¹ is hydrogen;

R₂₂ is chosen from hydroxy, lower alkoxy and —NR₁₃R₁₄; or together, R²¹and R²² form a carbonyl or a vinyl substituent.

andV. morphinans wherein R⁴ and R¹¹ form an additional sixth ring, whichmay be saturated or

unsaturated:

In another aspect, the invention relates to a method for preparing asecond compound that interacts with an opioid receptor when a firstcompound that interacts with an opioid receptor is known. When the firstcompound contains a phenolic hydroxyl, the method comprises convertingthe phenolic hydroxyl to a residue of structure:

which will hereinafter be sometimes referred to as Q.

In another aspect, the invention relates to methods for inhibiting,eliciting or enhancing responses mediated by an opioid receptorcomprising:

-   -   (a) providing a first compound that inhibits, elicits or        enhances an opioid receptor response;    -   (b) preparing a second compound that interacts with an opioid        receptor by converting a phenolic hydroxyl group on the first        compound to a residue described as Q above; and    -   (c) bringing the second compound into contact with the opioid        receptor.

In another aspect, the invention relates to a method for treating adisease by altering a response mediated by an opioid receptor. Themethod comprises bringing into contact with the opioid receptor acompound having the formula

whereinB represents the appropriate residue of a known compound of formula

and the known compound of that formula alters a response mediated by anopioid receptor.

DETAILED DESCRIPTION OF THE INVENTION

From many years of SAR studies, it is known that the hydroxyl ofmorphinans and benzomorphans interacts with a specific site in theopiate receptor. We have now surprisingly found that the hydroxyl can bereplaced with a very large carboxamide residue. A fairly wide range ofsecondary carboxamides exhibit binding in the desired range below 25nanomolar.

Since phenolic hydroxyls of benzomorphans and morphinans can bechemically converted to carboxamides by a simple, flexible andconvenient route described in U.S. Pat. Nos. 6,784,187 and 7,057,035,the door is opened to a whole family of new therapeutic agents, many ofwhich derive directly from the application of the principles set forthherein to known therapeutic agents that rely on opioid binding for theiractivity. Moreover, since the receptor seems to tolerate some variationin Q, one may contemplate further modulating receptor specificity,affinity and tissue distribution by varying the properties of the arylsubstituents.

In one aspect the invention relates to compounds of formula

In one major subclass, R¹¹ is

and the compounds are biphenyls, diaryl ethers and the like of formula:

Preferred values of Q

are those in which(a)

is phenyl, R¹⁰ is hydrogen and R¹¹ is

so that R¹¹ represents pyridinyl, phenyl, halophenyl, methylphenyl,methoxyphenyl (in all of which A′ is a direct bond) and phenoxy (inwhich A′ is —O—).(b)

is chosen from phenyl, naphthyl, fluorenyl, carbazole, dibenzofuran anddibenzothiophene, R¹⁰ is hydrogen, methoxy, halogen or methyl; and R¹¹is hydrogen;(c)

is pyridinyl, R¹⁰ is hydrogen and R¹¹ is chosen from phenyl, halophenyl,methylphenyl, methoxyphenyl and phenoxy.

It is known in the art that compounds that are μ, δ and κ agonistsexhibit analgesic activity; compounds that are selective μ agonistsexhibit anti-diarrheal activity and are useful in treating dyskinesia; μantagonists and κ agonists are useful in treating heroin, cocaine,alcohol and nicotine addiction; κ agonists are also anti-pruritic agentsand are useful in treating hyperalgesia. Recently it has been found[Peterson et al. Biochem. Pharmacol. 61, 1141-1151 (2001)] that κagonists are also useful in treating retroviral inflections. In general,the dextrorotatory isomers of morphinans of type III above are useful asantitussives and anticonvulsants.

Opioid receptor ligands having known high affinity are shown in thefollowing charts. Replacement of OH with Q in these compounds producescompounds that exhibit similar activity and better bioavailability.

Other opioid receptor ligands are described in Aldrich, J. V.“Analgesics” in Burger's Medicinal Chemistry and Drug Discovery, M. E.Wolff ed., John Wiley & Sons 1996, pages 321-44, the disclosures ofwhich are incorporated herein by reference. In all but two of theforegoing compounds, there is a single phenolic OH that is to bereplaced by Q according to the present invention. In norbinaltorphimineand 361444-66-8, there are two phenolic OH's, either or both of whichare replaced by Q.

We have examined the opioid receptor binding of a series of analogs ofknown compounds that interact at opioid receptors in which the OH isreplaced by the Q-group shown in Tables 1-3. Binding assays used toscreen compounds are similar to those previously reported by Neumeyer etal., Design and Synthesis of Novel Dimeric Morphinan Ligands for κ and μOpioid Receptors. J. Med. Chem. 2003, 46, 5162. Membrane protein fromCHO cells that stably expressed one type of the human opioid receptorwere incubated with 12 different concentrations of the compound in thepresence of either 1 nM [³H]U69,593¹⁰ (κ), 0.25 nM [³H]DAMGO¹¹ (μ) or0.2 nM [³H]naltrindole¹² (δ) in a final volume of 1 mL of 50 mMTris-HCl, pH 7.5 at 25° C. Incubation times of 60 min were used for[³H]U69,593 and [³H]DAMGO. Because of a slower association of[³H]naltrindole with the receptor, a 3 h incubation was used with thisradioligand. Samples incubated with [³H]naltrindole also contained 10 mMMgCl₂ and 0.5 mM phenylmethylsulfonyl fluoride. Nonspecific binding wasmeasured by inclusion of 10 μM naloxone. The binding was terminated byfiltering the samples through Schleicher & Schuell No. 32 glass fiberfilters using a Brandel 48-well cell harvester. The filters weresubsequently washed three times with 3 mL of cold 50 mM Tris-HCl, pH7.5, and were counted in 2 mL Ecoscint A scintillation fluid. For[³H]naltrindole and [³H]U69,593 binding, the filters were soaked in 0.1%polyethylenimine for at least 60 min before use. IC₅₀ valueswere-calculated by least squares fit to a logarithm-probit analysis.K_(i) values of unlabeled compounds were calculated from the equationK_(i)=(IC₅₀)/1+S where S=(concentration of radioligand)/(K_(d) ofradioligand).¹³ Data are the mean±SEM from at least three experimentsperformed in triplicate.

[³⁵S]GTPγS Binding Assays. In a final volume of 0.5 mL, 12 differentconcentrations of each test compound were incubated with 15 μg (κ), 10μg (δ) or 7.5 μg (μ) of CHO cell membranes that stably expressed eitherthe human κ, δ or μ opioid receptor. The assay buffer consisted of 50 mMTris-HCl, pH 7.4, 3 mM MgCl₂, 0.2 mM EGTA, 3 μM GDP, and 100 mM NaCl.The final concentration of [³⁵S]GTPγS was 0.080 nM. Nonspecific bindingwas measured by inclusion of 10 μM GTPγS. Binding was initiated by theaddition of the membranes. After an incubation of 60 min at 30° C., thesamples were filtered through Schleicher & Schuell No. 32 glass fiberfilters. The filters were washed three times with cold 50 mM Tris-HCl,pH 7.5, and were counted in 2 mL of Ecoscint scintillation fluid. Dataare the mean E. and EC₅₀ values±S.E.M. from at least three separateexperiments, performed in triplicate. For calculation of the E_(max)values, the basal [³⁵S]GTPγS binding was set at 0%. To determineantagonist activity of a compound at the μ opioid receptors, CHOmembranes expressing the μ opioid receptor, were incubated with 12different concentrations of the compound in the presence of 200 nM ofthe μ agonist DAMGO. To determine antagonist activity of a compound atthe κ opioid receptors, CHO membranes expressing the κ opioid receptor,were incubated with the compound in the presence of 100 nM of the κagonist U50,488. To determine if a compound was an antagonist at 6receptors, CHO membranes expressing the 6 receptor were incubated with12 different concentrations of the test compound in the presence of 10nM of the 6-selective agonist SNC 80.

TABLE 1 Cyclazocine subseries

Example optical [³H] [³H] [³H] # isomer Q DAMGO (μ) Naltrindole (δ)U69,593 (κ) 15 (±)− CONH(CH₂)₂(4-C₆H₄C₆H₅) 0.048 ± 0.0014 0.94 ± 0.045 0.33 ± 0.015 42 (±)− CONH(CH₂)₂(4-C₆H₄C₆H₅)  0.30 ± 0.036 0.74 ± 0.019 1.8 ± 0.19 43 (±)− CONH(CH₂)₂(4-C₆H₄C₆H₅)  0.26 ± 0.006 0.70 ± 0.073 2.3 ± 0.048 16 (−)− CONH(CH₂)₂(4-C₆H₄C₆H₅) 0.017 ± 0.004 0.32 ± 0.080.046 ± 0.01 16 (−) CONH(CH₂)₂(4-C₆H₄C₆H₅)  0.25 ± 0.031 0.24 ± 0.014 0.35 ± 0.009 17 (+)− CONH(CH₂)₂(4-C₆H₄C₆H₅)  7.8 ± 2.0   21 ± 0.74   11± 1.3 17 (+) CONH(CH₂)₂(4-C₆H₄C₆H₅)  6.4 ± 0.50  9.9 ± 0.44  8.5 ± 1.0718 (±)− CONH(CH₂)₃(4-C₆H₄C₆H₅)  5.8 ± 0.31   72 ± 11  2.7 ± 0.21 19 (±)−CON(CH₃)(CH₂)₂(4-C₆H₄C₆H₅)  6.7 ± 1.7   12 ± 2.4   11 ± 0.44 44 (±)−CONH-c-C₃H₄-(4-C₆H₄C₆H₅)(trans)   13 ± 0.69   20 ± 2.9   36 ± 6.8 45(±)− CONH-c-C₃H₄-(4-C₆H₄C₆H₅)(cis)   12 ± 2.4   20 ± 1.4   21 ± 4.8 46(±)− CONHCH₂CH(CH₃)(4-C₆H₄C₆H₅)   18 ± 1.1   12 ± 0.11   15 ± 1.0 47(±)− CONHCH(CH₃)CH₂(4-C₆H₄C₆H₅)  7.8 ± 0.99  7.6 ± 0.51   11 ± 0.24 48(±)− CONH(CH₂)₂(4-C₆H₄-4-CH₃OC₆H₄) 0.084 ± 0.012 0.18 ± 0.022  1.5 ±0.10 49 (±)− CONH(CH₂)₂(4-C₆H₄-4-ClC₆H₄)  0.20 ± 0.038 0.71 ± 0.046  3.2± 0.67 50 (±)− CONH(CH₂)₂(4-C₆H₄-3-ClC₆H₄)  0.56 ± 0.087  1.3 ± 0.19 3.8 ± 0.13 51 (±)− CONH(CH₂)₂(4-C₆H₄-4-CH₃C₆H₄)  0.29 ± 0.075 0.72 ±0.027  3.3 ± 0.20 52 (±)− CONH(CH₂)₂(2-Br-C₆H₄)  4.0 ± 0.36  150 ± 6.2  19 ± 1.3 30 (±)− CONH(CH₂)₂(3-Br-C₆H₄)  0.35 ± 0.021  3.5 ± 0.19 0.063± 0.006 29 (±)− CONH(CH₂)₂(4-Br-C₆H₄)  2.4 ± 0.33  2.5 ± 0.28  0.38 ±0.060 53 (±)− CONH(CH₂)₂(4-C₆H₄)CONH(CH₂)₂(4-BrC₆H₄)  1.5 ± 0.18   30 ±1.8  5.0 ± 0.36 37 (±)− CONH(CH₂)₂(2-naphthyl)  0.18 ± 0.009 0.90 ±0.020  0.20 ± 0.056 38 (±)− CONH(CH₂)₃(2-naphthyl)  1.9 ± 0.19   18 ±1.2  0.18 ± 0.016 40 (±)− CONH(CH₂)₂(1-naphthyl)  4.2 ± 0.13   24 ± 1.2 2.4 ± 0.46 41 (±)− CONH(CH₂)₃(1-naphthyl)  2.4 ± 0.45   18 ± 1.0  1.9 ±0.077 25 (±)− CONH(CH₂)₂(3-C₆H₄C₆H₅)  0.95 ± 0.15  5.9 ± 1.2  2.2 ± 0.1426 (±)− CONH(CH₂)₂(2-C₆H₄C₆H₅)  6.7 ± 0.49   21 ± 3.1  2.4 ± 0.28 33(±)− CONH(CH₂)₂(4-C₆H₄-O-C₆H₅) 0.059 ± 0.017  3.2 ± 0.30  1.6 ± 0.30 35(±)− CONH(CH₂)₂(3-C₆H₄-O-C₆H₅)  0.63 ± 0.090   12 ± 1.9  0.85 ± 0.070 34(±)− CONH(CH₂)₂(2-C₆H₄-O-C₆H₅)  0.54 ± 0.16   95 ± 6.7   13 ± 0.67 54(±)− CONH(CH₂)₂(4-C₆H₄-4-pyridinyl) 0.065 ± 0.0089  6.7 ± 0.58  1.8 ±0.12 55 (±)− CONH(CH₂)₂(4-C₆H₄-3-pyridinyl) 0.064 ± 0.0051  8.2 ± 0.50 2.2 ± 0.043 56 (±)− CONH(CH₂)₂(4-C₆H₄-2-pyridinyl)  0.33 ± 0.032  9.2 ±1.3  3.3 ± 0.089 57 (±)− CONH(CH₂)₂(3-pyridinyl-4-C₆H₅)  0.61 ± 0.14  14 ± 1.2  2.6 ± 0.12 58 (±)− CONH(CH₂)₂(2-pyridinyl-4-C₆H₅)  0.82 ±0.095  6.5 ± 0.81  1.4 ± 0.16 59 11 (±)− CONH(CH₂)₂C₆H₅  3.5 ± 0.27   59± 6.6  1.7 ± 0.18 12 (±)− CONH(CH₂)₃C₆H₅  2.5 ± 0.27   47 ± 1.6  3.0 ±0.35 60 (±)− CONH(CH₂)₄C₆H₅  4.3 ± 0.42  7.1 ± 0.39 0.082 ± 0.0026 61(±)− CONH(CH₂)₅C₆H₅  1.7 ± 0.15  7.9 ± 0.12  1.5 ± 0.10 62 (±)−CONH(CH₂)₆C₆H₅ NT NT NT 63 (±)− CONH(CH₂)₂-4-Cl-C₆H₄ NT NT NT 64 (±)−CONH(CH₂)₂-4-CH₃O-C₆H₄ NT NT NT 65 (±)− CONH(CH₂)₂-4-CH₃-C₆H₄ NT NT NT66 (±)− CONH(CH₂)₂-3,4-Cl₂-C₆H₃ NT NT NT 27 (±)−CONH(CH₂)₂(4-C₆H₄CH₂C₆H₅)  0.23 ± 0.032  5.9 ± 0.70  1.6 ± 0.27 67 (−)−CONHCH(S—CH₃)C₆H₅   28 ± 1.4 >10 μM   130 ± 4.0 68 (−)−CONHCH(R—CH₃)C₆H₅   62 ± 3.3 >10 μM   64 ± 4.3 69 (±)− CONHCH₂CH₂-3-pyr  120 ± 3.6   54 ± 1.3   97 ± 3.1 13 (±)− CONH(CH₂)₂(4-Br-3-pyridinyl)14 (±)− CONHCH₂CH₂-(4-Br-2-pyr)

TABLE 2 Keto subseries:

[³H] [³H] [³H] DAMGO Naltrindole U69,593 example Q = (μ) (δ) (κ) 20CONH(CH₂)₂(4- 3.1 ± 1.3  3.9 ± 1.4  1.3 ± 0.072 C₆H₄C₆H₅ (KC) 21CONH(CH₂)₂(4- 4.9 ± 0.20  13 ± 2.5 5.1 ± 0.18 C₆H₄C₆H₅ (EKC)

TABLE 3 Other Opioid Parents

[³H] [³H] [³H] exam- Q = CONH(CH₂)₂(4- DAMGO Naltrindole U69,593 pleC₆H₄C₆H₅ (μ) (δ) (κ) 70 naltrexone 0.11 ± 0.006  11 ± 1.1 0.31 ± 0.03 71Q-naltrexone 1.4 ± 0.12  34 ± 4.1  22 ± 1.4 72 naltrindole 13 ± 1.1 0.13 ± 0.02  4.6 ± 0.23 73 Q-naltrindole NT NT NT 74 buprenorphine 0.21± 0.024  2.9 ± 0.49  0.62 ± 0.073 75 Q-buprenorphine  1.3 ± 0.072  16 ±1.9 120 ± 15  76 nalbuphine 1.6 ± 0.37 580 ± 80   3.0 ± 0.63 77Q-nalbuphine 5.2 ± 0.07  82 ± 3.3  82 ± 5.8 78 butorphanol 0.12 ± 0.058 12 ± 3.8  0.22 ± 0.023 79 Q-butorphanol 0.32 ± 0.048  0.45 ± 0.039  3.9± 0.47 80 naltrexone ring opened 17 ± 4.0  130 ± 6.6   2.2 ± 0.16 81Q-naltrexone ring 0.71 ± 0.091  3.7 ± 0.20  1.9 ± 0.15 opened

Antinociceptive activity is evaluated by the method described in Jianget al. [J. Pharmacol. Exp. Ther. 264, 1021-1027 (1993), page 1022]. TheED₅₀'s of compounds of the invention are expected to be under 100 nmolin the mouse acetic acid writhing test when administered i.c.v., and anincrease in the duration of action is expected for compounds of theinvention compared to their “parents” when given by i.p. administration.

DEFINITIONS

Throughout this specification the terms and substituents retain theirdefinitions.

Alkyl is intended to include linear, branched, or cyclic hydrocarbonstructures and combinations thereof. Lower alkyl refers to alkyl groupsof from 1 to 6 carbon atoms. Examples of lower alkyl groups includemethyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, s- and t-butyl,cyclobutyl and the like. Preferred alkyl groups are those of C₂₀ orbelow. Cycloalkyl is a subset of alkyl and includes cyclic hydrocarbongroups of from 3 to 8 carbon atoms. Examples of cycloalkyl groupsinclude c-propyl, c-butyl, c-pentyl, norbornyl and the like.

Alkoxy or alkoxyl refers to groups of from 1 to 8 carbon atoms of astraight, branched, cyclic configuration and combinations thereofattached to the parent structure through an oxygen. Examples includemethoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy andthe like. Lower-alkoxy refers to groups containing one to four carbons.

Aryl and heteroaryl mean a 5- or 6-membered aromatic or heteroaromaticring containing 0-3 heteroatoms selected from O, N, or S; a bicyclic 9-or 10-membered aromatic or heteroaromatic ring system containing 0-3heteroatoms selected from O, N, or S; or a tricyclic 13- or 14-memberedaromatic or heteroaromatic ring system containing 0-3 heteroatomsselected from O, N, or S. The aromatic 6- to 14-membered carbocyclicrings include, e.g., benzene, naphthalene, indane, tetralin, andfluorene and the 5- to 10-membered aromatic heterocyclic rings include,e.g., imidazole, pyridine, indole, thiophene, benzopyranone, thiazole,furan, benzimidazole, quinoline, isoquinoline, quinoxaline, pyrimidine,pyrazine, tetrazole and pyrazole.

Arylalkyl means an alkyl residue attached to an aryl ring. Examples arebenzyl, phenethyl and the like. Heteroarylalkyl means an alkyl residueattached to a heteroaryl ring. Examples include, e.g., pyridinylmethyl,pyrimidinylethyl and the like.

Heterocycle means a cycloalkyl or aryl residue in which one to two ofthe carbons is replaced by a heteroatom such as oxygen, nitrogen orsulfur. Heteroaryls form a subset of heterocycles. Examples ofheterocycles that fall within the scope of the invention includepyrrolidine, pyrazole, pyrrole, indole, quinoline, isoquinoline,tetrahydroisoquinoline, benzofuran, benzodioxan, benzodioxole (commonlyreferred to as methylenedioxyphenyl, when occurring as a substituent),tetrazole, morpholine, thiazole, pyridine, pyridazine, pyrimidine,thiophene, furan, oxazole, oxazoline, isoxazole, dioxane,tetrahydrofuran and the like.

Substituted alkyl, aryl, cycloalkyl, or heterocyclyl refer to alkyl,aryl, cycloalkyl, or heterocyclyl wherein up to three H atoms in eachresidue are replaced with halogen, hydroxy, loweralkoxy, carboxy,carboalkoxy, carboxamido, cyano, carbonyl, —NO₂, —NR¹R²; alkylthio,sulfoxide, sulfone, acylamino, amidino, phenyl, benzyl, heteroaryl,phenoxy, benzyloxy, heteroaryloxy, or substituted phenyl, benzyl,heteroaryl, phenoxy, benzyloxy, or heteroaryloxy.

Virtually all of the compounds described herein contain one or moreasymmetric centers and may thus give rise to enantiomers, diastereomers,and other stereoisomeric forms that may be defined, in terms of absolutestereochemistry, as (R)- or (S)-. The present invention is meant toinclude all such possible isomers, as well as their racemic andoptically pure forms. In general it has been found that the levo isomerof morphinans and benzomorphans is the more potent antinociceptiveagent, while the dextro isomer may be useful as an antitussive orantispasmodic agent. Optically active (R)- and (S)-isomers may beprepared using chiral synthons or chiral reagents, or resolved usingconventional techniques. When the compounds described herein containolefinic double bonds or other centers of geometric asymmetry, andunless specified otherwise, it is intended that the compounds includeboth E and Z geometric isomers. Likewise, all tautomeric forms are alsointended to be included.

Abbreviations

The following abbreviations and terms have the indicated meaningsthroughout:

-   Ac=acetyl-   BNB=4-bromomethyl-3-nitrobenzoic acid-   Boc=t-butyloxy carbonyl-   Bu=butyl-   c-=cyclo-   DAMGO=Tyr-ala-Gly-NMePhe-NHCH₂OH-   DBU=diazabicyclo[5.4.0]undec-7-ene-   DCM=dichloromethane=methylene chloride=CH₂C₁₂-   DEAD=diethyl azodicarboxylate-   DIC=diisopropylcarbodiimide-   DIEA=N,N-diisopropylethyl amine-   DMAP=4-N,N-dimethylaminopyridine-   DMF=N,N-dimethylformamide-   DMSO=dimethyl sulfoxide-   DPPF=1,1′-bis(diphenylphosphino)ferrocene-   DVB=1,4-divinylbenzene-   EEDQ=2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline-   Fmoc=9-fluorenylmethoxycarbonyl-   GC=gas chromatography-   HATU═O-(7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium-   hexafluorophosphate-   HOAc=acetic acid-   HOBt=hydroxybenzotriazole-   Me=methyl-   mesyl=methanesulfonyl-   MTBE=methyl t-butyl ether-   NMO=N-methylmorpholine oxide-   PEG=polyethylene glycol-   Ph=phenyl-   PhOH=phenol-   PfP=pentafluorophenol-   PPTS=pyridinium p-toluenesulfonate-   PyBroP=bromo-tris-pyrrolidino-phosphonium hexafluorophosphate-   rt=room temperature-   sat′ d=saturated-   s-=secondary-   t-=tertiary-   TBDMS=t-butyldimethylsilyl-   TFA=trifluoroacetic acid-   THF=tetrahydrofuran-   TMOF=trimethyl orthoformate-   TMS=trimethylsilyl-   tosyl=p-toluenesulfonyl-   Trt=triphenylmethyl

It may happen that residues in the substrate of interest requireprotection and deprotection during the conversion of the phenol to thedesired Q. Terminology related to “protecting”, “deprotecting” and“protected” functionalities occurs throughout this application. Suchterminology is well understood by persons of skill in the art and isused in the context of processes which involve sequential treatment witha series of reagents. In that context, a protecting group refers to agroup which is used to mask a functionality during a process step inwhich it would otherwise react, but in which reaction is undesirable.The protecting group prevents reaction at that step, but may besubsequently removed to expose the original functionality. The removalor “deprotection” occurs after the completion of the reaction orreactions in which the functionality would interfere. Thus, when asequence of reagents is specified, as it is below, the person ofordinary skill can readily envision those groups that would be suitableas “protecting groups”. Suitable groups for that purpose are discussedin standard textbooks in the field of chemistry, such as ProtectiveGroups in Organic Synthesis by T.W. Greene [John Wiley & Sons, New York,1991], which is incorporated herein by reference.

The compounds of the invention are synthesized by one of the routesdescribed below:

In general, the intermediate N-hydroxysuccinimide ester intermediates(3) shown in scheme 1 are prepared by the processes of U.S. Pat. No.7,057,0357, the contents of which are incorporated herein by reference.The N-hydroxysuccinimide ester is then reacted with the appropriatearylalkylamine (4) as described below. An alternative, employing directcarbonylation/amidation is shown in Scheme 2. Many diaryl compounds canbe prepared by Suzuki coupling, shown in Scheme 3.

Proton NMR spectra and in certain cases ¹³C NMR were obtained on aVarian Unity-300 or 500 NMR spectrometer with tetramethylsilane as aninternal reference for samples dissolved in CDCl₃. Samples dissolved inCD₃OD and DMSO-d₆ were referenced to the solvent. Proton NMRmultiplicity data are denoted by s (singlet), d (doublet), t (triplet),q (quartet), m (multiplet), dd (doublet of doublets), and br (broad).Coupling constants are in hertz. Direct insertion probe chemicalionization mass spectral data were obtained on a Shimadzu GC-17A GC-MSmass spectrometer. Direct infusion electrospray ionization (inpositively charged ion mode) mass spectral data were obtained on anAgilent 1100 series LC/MSD system (Germany). Melting points weredetermined on a Meltemp capillary melting point apparatus and wereuncorrected. Infrared spectral data were obtained on a Perkin-ElmerParagon 1000 FT-IR spectrophotometer. Optical rotation data was obtainedfrom a Perkin-Elmer 241 polarimeter. The assigned structure of all testcompounds and intermediates were consistent with the data. Carbon,hydrogen, and nitrogen elemental analyses for all novel targets wereperformed by Quantitative Technologies Inc., Whitehouse, N.J., and werewithin ±0.4% of theoretical values except as noted; the presence ofwater or other solvents was confirmed by proton NMR. Reactions weregenerally performed in an argon or nitrogen atmosphere. Commerciallypurchased chemicals were used without purification unless otherwisenoted. The following reagents were purchased from Aldrich ChemicalCompany: N-hydroxysuccinimide, phenethylamine, 3-phenyl-1-propylamine,4-aminobiphenyl, palladium acetate, 4-phenylbenzylamine and benzylamine. The following reagent was purchased from Trans World Chemicals:2-(4-biphenyl ethylamine). The following reagents were purchased fromStrem Chemicals, Incorporated: 1,1′-bis(diphenyl-phosphino)ferrocene(dppf) and dichloro[1,1′-bis(diphenylphosphino)-ferrocene]palladium (II)dichloromethane adduct [PdCl₂(dppf)]. Pyridine was distilled from KOH.DMF and DMSO were distilled over CaH₂ under reduced pressure. Silica gel(Bodman Industries, ICN SiliTech 2-63 D 60A, 230-400 Mesh) was used forall flash chromatography. Amines were purchased from Aldrich ChemicalCompany and used as received unless otherwise indicated. Toluene andEt₂O were distilled from sodium metal. THF was distilled fromsodium/benzophenone ketyl. Pyridine was distilled from KOH. Methylenechloride was distilled from CaH₂. DMF and DMSO were distilled from CaH₂under reduced pressure. Methanol was dried over 3±molecular sieves priorto use. Silica gel (Bodman Industries, ICN SiliTech 2-63 D 60A, 230-400Mesh) was used for flash column chromatography.

(±)-1-[[[3-(Cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-2,6-methano-3-benzazocin-8-yl]carbonyl]oxy]-2,5-Pyrrolidinedione[(3) R³=CH₂c-C₃H₅; R², R^(2a), R⁴ and R⁷═H; R⁵ and R⁶═CH₃.] To a flaskcharged with triflate [(2) R³=CH₂c-C₃H₅; R², R^(2a), R⁴ and R⁷═H; R⁵ andR⁶═CH₃] (403 mg, 1.00 mmol), N-hydroxy succinimide (230 mg, 2.00 mmol)palladium acetate (22.4 mg, 0.10 mmol) and dppf (55.4 mg, 0.10 mmol) wasadded triethyl amine (0.28 mL, 2.00 mmol). The reaction was equippedwith a condenser and sealed with a septum and a balloon. The wholesystem was vacuumed and backfilled with nitrogen for three cycles. DMSO(1 mL) was added via syringe. Then it was vacuumed again and backfilledwith a mixture of carbon monoxide. The resulting mixture was heated at70° C. for 8.5 h. The cooled reaction mixture was diluted with ethylacetate (30 mL), washed with water, and brine. The organic phase wasdried over sodium sulfate, filtered, and concentrated to give a brownoil, which was purified by flash chromatography (Ethylacetate:Acetone:Hexane:Et₃N 2:1:0.4:0.03) to give 3 as a white foam (217mg, 0.55 mmol, 55%): ¹H NMR (500 MHz, CDCl₃) δ 7.96 (d, 1H, J=1.5 Hz),7.82 (dd, 1H, J₁=1.5 Hz, J₂=8.1 Hz), 7.17 (d, 1H, J=8.1 Hz), 3.19 (m,1H), 2.97 (d, 1H, J=19.5 Hz), 2.85 (s, 4H), 2.73 (m, 2H), 2.44 (dd, 1H,J₁=6.4 Hz, J₂=12.7 Hz), 2.33 (dd, 1H, J₁=6.6 Hz, J₂=12.4 Hz), 1.93 (m,1H), 1.84 (d, 2H, J=8.5 Hz), 1.35 (s, 3H), 1.27 (m, 1H), 0.83 (m, 1H),0.79 (d, 3H, J=7.1 Hz), 0.48 (m, 2H), 0.08 (m, 2H). MS (ESI) m/z 397(M+H)⁺¹; Anal. Calcd. for C₂₃H₂₈N₂O₄. 0.5H₂O: C, 68.20; H, 7.20; N;6.90. Found: C, 68.04; H, 6.92; N, 7.12.

(±)-3-(Cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-N-(2-[1,1′-biphenyl]-4-ylethyl)-2,6-methano-3-benzazocine-8-carboxamide(15).

Method A. Conditions similar to those previously reported by Wentland etal. [Bioorgan. Med. Chem. Lett. 2001, 11, 623-626] were used. A solutionof (±)-3 (140 mg, 0.35 mmol) and 2-(4-biphenyl ethylamine) (84 mg, 0.42mmol) in 2.5 mL of dry pyridine was stirred at room temperature for 48h. The solvent was removed in vacuo and the residue was taken up inmethylene chloride (40 mL), washed once with saturated sodiumbicarbonate solution, water, and brine. The organic phase was dried oversodium sulfate, filtered, and concentrated to give a brown residue,which was purified by flash chromatography (CH₂C₁₂:CH₃OH:NH₄OH 15:1:0.1)to give 15 as an off-white foam (110 mg, 0.23 mmol, 66%). ¹H NMR (500MHz, CDCl₃) δ 7.66 (d, 1H, J=1.5 Hz), 7.57 (dd, 2H, J₁=1.3 Hz, J₂=7.5Hz), 7.55 (d, 2H, J=8.5 Hz), 7.43 (t, 2H, J=7.75 Hz), 7.39 (dd, 1H,J₁=1.8 Hz, J₂=7.75 Hz), 7.34 (t, 1H, J=7.5 Hz), 7.31 (d, 2H, J=8 Hz),7.08 (d, 1H, J=8 Hz), 6.32 (bt, 1H, J=5.75 Hz), 3.72 (q, 2H, J=6.7 Hz),3.14 (m, 1H), 2.97 (t, 2H, J=1.5 Hz), 2.93 (d, 1H, J=18.5 Hz), 2.70 (m,2H), 2.45 (dd, 1H, J₁=6.3 Hz, J₂=12.75 Hz), 2.34 (dd, 1H, J₁=6.75 Hz,J₂=12.75 Hz), 1.93 (m, 3H), 1.39 (s, 3H), 1.32 (d, 1H, J=9.5), 0.87 (m,1H), 0.81 (d, 3H, J=7.0 Hz), 0.50 (dd, 2H, J₁=1.5 Hz, J₂=8.0 Hz), 0.12(m, 2H). MS (ESI) m/z 479 (M+H)⁺; Anal. Calcd. for C₃₃H₃₈N₂O.1.0H₂O: C,79.80; H, 8.12; N, 5.64. Found: C, 79.72; H, 8.07; N, 5.96.

(±)-3-(Cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-N-(2-phenylethyl)-2,6-methano-3-benzazocine-8-carboxamide(11). This compound was prepared using Method A and phenethylamine.Off-white foam (93 mg, 0.231 mmol, 83%). ¹H NMR (500 MHz, CDCl₃) δ 7.61(d, 1H, J=2.0 Hz), 7.35 (m, 3H), 7.26 (m, 3H), 7.08 (d, 1H, J=8 Hz),6.07 (bt, 1H, J=5.0 Hz), 3.71 (q, 2H, J=6.5 Hz), 3.16 (m, 1H), 2.94 (m,3H), 2.70 (m, 2H), 2.47 (m, 1H), 2.32 (m, 1H), 1.93 (m, 3H), 1.40 (s,3H), 1.33 (d, 1H, J=11.5), 0.87 (m, 1H), 0.82 (d, 3H, J=7.0 Hz), 0.52(d, 2H, J=8.0 Hz), 0.11 (m, 2H); MS (ESI) m/z 403 (M+H)⁺; Anal. Calcd.for C₂₇H₃₄N₂O.0.5H₂O: C, 78.79; H, 8.57; N, 6.81. Found: C, 78.90; H,8.55; N, 6.86.

(±)-3-(Cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-N-(3-phenylpropyl)-2,6-methano-3-benzazocine-8-carboxamide(12). This compound was prepared using Method A and3-phenyl-1-propylamine. Off-white foam (72 mg, 0.174 mmol, 68%). ¹H NMR(500 MHz, CDCl₃) δ 7.66 (d, 1H, J=1.5 Hz), 7.30 (m, 3H), 7.21 (m, 3H),7.09 (d, 1H, J=8 Hz), 6.02 (bt, 1H, J=5.5 Hz), 3.50 (q, 2H, J=6.8 Hz),3.15 (m, 1H), 2.95 (d, 1H, J=19.0 Hz), 2.71 (m, 4H), 2.46 (m, 1H), 2.32(m, 1H), 1.94 (m, 5H), 1.42 (s, 3H), 1.34 (d, 1H, J=9.75), 0.87 (m, 1H),0.82 (d, 3H, J=7.0 Hz), 0.51 (d, 2H, J=8.0 Hz), 0.11 (m, 2H); MS (ESI)m/z 417 (M+H)⁺; Anal. Calcd. for C₂₈H₃₆N₂O.0.33H₂O: C, 79.58; H, 8.75;N, 6.63. Found: C, 79.71; H, 8.75; N, 6.66.

(−)-3-(Cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-N-(2-[1,1′-biphenyl]-4-ylethyl)-2,6-methano-3-benzazocine-8-carboxamide[0-16]. Method B. Conditions similar to those previously reported wereused. 2-(4-Biphenyl ethylamine) (85 mg, 0.43 mmol) PdCl₂(dppf) (16 mg,0.02 mmol) were added to a two-neck flask charged with triflate ester of(−)-cyclazocine⁵ (158 mg, 0.39 mmol). The reaction was equipped with acondenser and sealed with a septum and a balloon. The whole system wasvacuumed and backfilled with nitrogen for three cycles. DMF (2 mL) andtriethylamine (0.09 mL, 0.62 mmol) were added via syringe. Then it wasvacuumed again and backfilled with a mixture of carbon monoxide. Theresulting mixture was heated at 70° C. for 18 h. The cooled reactionmixture was diluted with ethyl acetate (30 mL), washed with saturatedbicarbonate solution, water, and brine. The organic phase was dried oversodium sulfate, filtered, and concentrated to give a black oil, whichwas purified by flash chromatography (CH₂C₁₂:CH₃OH:NH₄OH 25:1:0.1) togive (−)-16 as an off-white foam (100 mg, 0.21 mmol, 53%). ¹H NMR (300MHz, CDCl₃) δ 7.68 (s, 1H), 7.57 (m, 4H), 7.43 (m, 3H), 7.33 (m, 3H),7.08 (d, 1H, J=7.8 Hz), 6.34 (bt, 1H), 3.73 (q, 2H, J=6.0 Hz), 3.16 (m,1H), 2.94 (m, 3H), 2.71 (m, 2H), 2.48 (m, 1H), 2.31 (m, 1H), 1.93 (m,3H), 1.40 (s, 3H), 1.32 (m, 1H), 0.87 (m, 1H), 0.82 (d, 3H, J=7.2 Hz),0.51 (d, 2H, J=6.6 Hz), 0.11 (m, 2H). MS (ESI) m/z 479 (M+H)⁺; Anal.Calcd. for C₃₃H₃₈N₂O.1.25H₂O: C, 79.08; H, 8.14; N, 5.59. Found: C,79.23; H, 7.84; N, 5.57. For (−)-16: [α]²⁵ _(D)=−69.1° (c=0.75,acetone).

(+)-3-(Cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-N-(2-[1,1′-biphenyl]-4-ylethyl)-2,6-methano-3-benzazocine-8-carboxamide[(+)-17]. This compound was prepared using Method B and triflate esterof (+)-cyclazocine.5 Off-white foam (90 mg, 0.19 mmol, 49%). ¹H NMR (500MHz, CDCl₃) δ 7.68 (s, 1H), 7.57 (d, 2H, J=7.5 Hz), 7.55 (d, 2H, J=7.5Hz) 7.42 (m, 3H), 7.32 (m, 3H), 7.07 (d, 1H, J=8.0 Hz), 6.40 (bt, 1H),3.72 (q, 2H, J=6.0 Hz), 3.13 (m, 1H), 2.94 (m, 3H), 2.69 (m, 2H), 2.45(dd, 1H, J₁=6.5 Hz, J₂=13.0 Hz), 2.30 (dd, 1H, J₁=6.5 Hz, J₂=12.5 Hz),1.93 (m, 3H), 1.39 (s, 3H), 1.32 (m, 1H), 0.87 (m, 1H), 0.81 (d, 3H,J=7.0 Hz), 0.50 (d, 2H, J=8.0 Hz), 0.11 (m, 2H). MS (ESI) m/z 479(M+H)⁻¹; Anal. Calcd. for C₃₃H₃₈N₂O.0.67H₂O: C, 80.78; H, 8.07; N, 5.71.Found: C, 80.96; H, 8.13; N, 5.45. For (+)-17: [α]²⁵D=+81.3° (c=1.02,acetone).

3-[1,1′-biphenyl]-4-propylamine. To a vigorously stirred solution of4-biphenylacrylamide (440 mg, 1.97 mmol) in 10 mL of THF under nitrogenatmosphere was added 1.0 M lithium alumina hydride solution in THF (4.0mL, 4.0 mmol). The resulting mixture was stirred for 2 h at reflux. Thereaction was then cooled in an ice bath, quenched with water, dilutedwith ethyl acetate and filtered. The filtrate was washed with saturatedbicarbonate solution, water, and brine. The organic phase was dried overmagnesium sulfate, filtered, and concentrated to give an oil, which waspurified by flash chromatography (CH₂C₁₂:CH₃OH:NH₄OH 10:1:0.1) to give3-[1,1′-biphenyl]-4-propylamine as a clear oil (147 mg, 0.66 mmol, 34%):¹H NMR (300 MHz, CDCl₃) δ 7.59 (d, 2H, J=7.5 Hz), 7.53 (d, 2H, J=7.8Hz), 7.44 (t, 2H, J=7.65 Hz), 7.33 (m, 1H), 7.27 (d, 2H, J=7.5 Hz), 2.77(b, 2H), 2.71 (t, 2H, J=7.65 Hz), 1.99 (b, 2H), 1.82 (m, 2H); MS (ESI)m/z 212 (M+H)⁺; Anal. Calcd. for C₁₅H₁₇N.

(±)-3-(Cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-N-(3-[1,1′-biphenyl]-4-ylpropyl)-2,6-methano-3-benzazocine-8-carboxamide(18). This compound was prepared using Method B and3-[1,1′-biphenyl]-4-propylamine. Off-white foam (250 mg, 0.51 mmol,63%). ¹H NMR (500 MHz, CDCl₃) δ 7.68 (s, 1H), 7.57 (d, 2H, J=7.5 Hz),7.52 (d, 2H, J=7.5 Hz) 7.43 (t, 2H, J=7.75 Hz), 7.32 (m, 4H), 7.05 (d,1H, J=7.5 Hz), 6.09 (bt, 1H), 3.52 (q, 2H, J=6.7 Hz), 3.13 (m, 1H), 2.93(d, 1H, J=19 Hz), 2.77 (t, 2H, J=7.75 Hz), 2.67 (m, 2H), 2.45 (dd, 1H,J₁=6.0 Hz, J₂=12.5 Hz), 2.30 (dd, 1H, J₁=6.75 Hz, J₂=12.25 Hz), 1.93 (m,5H), 1.41 (s, 3H), 1.32 (m, 1H), 0.85 (m, 1H), 0.81 (d, 3H, J=7.5 Hz),0.51 (d, 2H, J=8.0 Hz), 0.10 (m, 2H). MS (ESI) m/z 493 (M+H)⁺; Anal.Calcd. for C₃₄H₄₀N₂O.0.75H₂O: C, 80.67; H, 8.26; N, 5.53. Found: C,80.78; H, 8.12; N, 5.51.

(±)-3-(Cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-N-(2-[1,1′-biphenyl]-4-ylethyl)-N-methyl-2,6-methano-3-benzazocine-8-carboxamide(19). This compound was prepared using Method B andN-methyl-[1,1′-biphenyl]-4-ethanamine. Off-white foam (190 mg, 0.39mmol, 60%). ¹H NMR (500 MHz, CDCl₃) δ 7.56 (m, 4H), 7.43 (m, 3H), 7.39(m, 1H), 7.33 (t, 2H, J=6.75 Hz), 7.22 (s, 1H), 7.05 (d, 1H, J=7.5 Hz),3.80 (b, 1H), 3.48 (b, 1H), 3.14 (b, 3H), 3.04 (b, 1H), 2.90 (m, 3H),2.70 (m, 2H), 2.47 (m, 1H), 2.32 (m, 1H), 1.93 (m, 3H), 1.35 (s, 3H),1.30 (d, 1H, J=12.5), 0.84 (m, 1H), 0.84 (d, 3H, J=6.5 Hz), 0.51 (d, 2H,J=7.5 Hz), 0.12 (m, 2H). MS (ESI) m/z 493 (M+H)⁺; Anal. Calcd. forC₃₄H₄₀N₂O.0.13H₂O: C, 82.51; H, 8.20; N, 5.66. Found: C, 82.33; H, 8.07;N, 5.69.

(±)-3-(Cyclopropylmethyl)-6-ethyl-1,2,3,4,5,6-hexaahydro-cis-11-methyl-N-(2-[1,1′-biphenyl]-4-ylethyl)-1-oxo-2,6-methano-3-benzazocine-8-carboxamide(21). This compound was prepared using Method B with the triflate esterof EKC and 2-(4-biphenyl ethylamine). Off-white foam (200 mg, 0.39 mmol,61%). ¹H NMR (500 MHz, CDCl₃) δ 8.00 (d, 1H, J=8.0 Hz), 7.82 (s, 1H),7.58 (m, 4H), 7.51 (d, 2H, J=8.0 Hz) 7.44 (t, 2H, J=7.5 Hz), 7.33 (m,3H), 6.19 (bt, 1H), 3.77 (q, 2H, J=6.5 Hz), 3.32 (d, 1H, J=8.0 Hz), 3.00(t, 2H, J=6.75 Hz) 2.92 (dd, 1H, J₁=3.75 Hz, J₂=12.25 Hz), 2.65 (dd, 2H,J₁=5.75 Hz, J₂=8.25 Hz), 2.36 (m, 1H), 2.29 (m, 1H), 2.10 (m, 1H), 1.97(dd, 1H, J₁=7.5 Hz, J₂=13.0 Hz), 1.90 (m, 1H), 1.82 (m, 1H), 1.24 (d,1H, J=12.0 Hz), 1.05 (t, 3H, J=7.75 Hz), 0.87 (m, 1H), 0.79 (d, 3H,J=7.0 Hz), 0.48 (m, 2H), 0.26 (m, 1H), 0.01 (m, 1H). MS (ESI) m/z 507(M+H)⁺; Anal. Calcd. for C₃₄H₃₈N₂O₂.1.35H₂O: C, 76.91; H, 7.73; N, 5.28.Found: C, 76.89; H, 7.48; N, 4.89.

(±)-3-(Cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-N-(2-(biphenyl-3-yl)ethyl)-2,6-methano-3-benzazocine-8-carboxamide(25). Method B Phenylboronic acid (38 mg, 0.31 mmol), 10 (100 mg, 0.21mmol), palladium acetate (5 mg, 0.02 mmol), triphenylphosphine (21 mg,0.08 mmol), 4N sodium carbonate (0.52 mmol) and toluene were places in amicrowave vial, sealed and heated at 120° C. for 20 min. The cooledreaction mixture was diluted with ethyl acetate (30 mL), washed withsaturated bicarbonate solution, water, and brine. The organic phase wasdried over sodium sulfate, filtered, and concentrated to give a blackoil, which was purified by flash chromatography (CH₂C₁₂:CH₃OH:NH₄OH25:1:0.1) to give 5 as an white foam (80 mg, 80%). ¹H NMR (500 MHz,CDCl₃) δ 7.61 (s, 1H), 7.56 (d, 2H, J=7.5 Hz), 7.47 (m, 2H), 7.42 (m,4H), 7.34 (t, 1H, J=7.3 Hz), 7.23 (d, 1H, J=7.5 Hz), 7.07 (d, 1H, J=7.5Hz), 6.18 (t, 1H, J=5.7 Hz), 3.72 (q, 2H, J=6.7 Hz), 3.14 (s, 1H), 2.97(t, 2H, J=1.5 Hz), 2.93 (d, 1H, J=18.5 Hz), 2.70 (m, 2H), 2.45 (dd, 1H,J₁=6.3 Hz, J₂=12.75 Hz), 2.34 (dd, 1H, J₁=6.75 Hz, J₂=12.75 Hz), 1.93(m, 3H), 1.39 (s, 3H), 1.27 (d, 1H, J=11.5), 0.87 (m, 1H), 0.81 (d, 3H,J=7.0 Hz), 0.50 (dd, 2H, J₁=1.5 Hz, J₂=8.0 Hz), 0.12 (m, 2H). MS (ESI)m/z 479 (M+H)+; Anal. Calcd. for C₃₃H₃₈N₂O.1.0H₂O: C, 79.80; H, 8.12; N,5.64. Found: C, 79.66; H, 7.85; N, 5.62.

(±)-3-(Cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-N-(2-(biphenyl-2-yl)ethyl)-2,6-methano-3-benzazocine-8-carboxamide(26). Prepared using Method B. White foam (70 mg, 70%). ¹H NMR (300 MHz,CDCl₃) δ 7.58 (s, 1H), 7.2-7.4 (m, 10H), 7.06 (d, 1H, J=7.8 Hz), 5.97(t, 1H, J=5.7 Hz), 3.50 (q, 2H, J=6.0 Hz), 3.14 (s, 1H), 2.94 (m, 3H),2.70 (m, 2H), 2.44 (dd, 1H, J₁=6 Hz, J₂=13 Hz), 2.31 (dd, 1H, J₁=6 Hz,J₂=13 Hz), 1.90 (m, 3H), 1.40 (s, 3H), 1.31 (m, 1H), 0.88 (m, 1H), 0.82(d, 3H, J=7.0 Hz), 0.50 (d, 2H, J=8.1 Hz), 0.12 (m, 2H). MS (ESI) m/z479 (M+H)+; Anal. Calcd. for C₃₃H₃₈N₂O.0.75H₂O: C, 80.53; H, 8.09; N,5.69. Found: C, 80.43; H, 8.10; N, 5.79.

(±)-3-(Cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-N-(4-benzylphenethyl)-2,6-methano-3-benzazocine-8-carboxamide(27). Prepared using Method A and 2-(4-benzylphenyl)ethanamine. Whitefoam (83 mg, 42%). ¹H NMR (300 MHz, CDCl₃) δ 7.60 (s, 1H), 7.35 (d, 1H,J=7.8 Hz), 7.28 (m, 2H), 7.17 (m, 7H), 7.07 (d, 1H, J=8.1 Hz), 6.08 (t,1H, J=6 Hz), 3.96 (s, 2H), 3.67 (q, 2H, J=6.5 Hz), 3.13 (s, 1H), 2.94(d, 1H, J=18.3 Hz), 2.89 (t, 2H, J=6.9 Hz), 2.68 (m, 2H), 2.46 (dd, 1H,J₁=6.5 Hz, J₂=12.5 Hz), 2.31 (dd, 1H, J₁=6.6 Hz, J₂=12.9 Hz), 1.90 (m,3H), 1.38 (s, 3H), 1.30 (d, 1H, J=11.1 Hz), 0.85 (m, 1H), 0.82 (d, 3H,J=7.0 Hz), 0.51 (d, 2H, J=8.0 Hz), 0.09 (m, 2H). MS (ESI) m/z 493(M+H)+; Anal. Calcd. for C₃₄H₄₀N₂O.0.4H₂O: C, 81.69; H, 8.23; N, 5.60.Found: C, 81.59; H, 8.26; N, 5.57.

(±)-3-(Cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-N-(4-bromophenethyl)-2,6-methano-3-benzazocine-8-carboxamide(29). Prepared using Method A and 2-(4-bromophenyl)ethanamine. Off-whitefoam (60 mg, 50%). ¹H NMR (300 MHz, CDCl₃) δ 7.63 (s, 1H), 7.42 (d, 2H,J=8.3 Hz), 7.35 (d, 1H, J=8.1 Hz), 7.09 (d, 2H, J=8.3 Hz), 7.07 (d, 1H,J=7.3 Hz), 6.21 (t, 1H, J=6 Hz), 3.65 (q, 2H, J=6.3 Hz), 3.15 (m, 1H),2.95 (d, 1H, J=19 Hz), 2.87 (t, 2H, J=7.0 Hz), 2.7 (m, 2H), 2.46 (dd,1H, J₁=6.4 Hz, J₂=12.7 Hz), 2.31 (dd, 1H, J₁=6.8 Hz, J₂=12.4 Hz), 1.90(m, 3H), 1.39 (s, 3H), 1.31 (m, 1H), 0.89 (m, 1H), 0.81 (d, 3H, J=7.2Hz), 0.50 (m, 2H), 0.10 (m, 2H). MS (ESI) m/z 481, 483 (M+H)+; Anal.Calcd. for C₂₇H₃₃N₂OBr.0.1H₂O: C, 67.10; H, 6.92; N, 5.80. Found: C,67.04; H, 6.80; N, 5.74.

(±)-3-(Cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-N-(3-bromophenethyl)-2,6-methano-3-benzazocine-8-carboxamide(20). Prepared using Method A and 2-(3-bromophenyl)ethanamine. Off-whitefoam (159 mg, 53%). ¹H NMR (300 MHz, CDCl₃) δ 7.62 (s, 1H), 7.42 (m,3H), 7.2 (m, 2H), 7.09 (d, 2H, J=7.8 Hz), 6.1 (t, 1H, J=6 Hz), 3.68 (q,2H, J=6.1 Hz), 3.15 (m, 1H), 2.95 (d, 1H, J=19 Hz), 2.91 (t, 2H, J=7.1Hz), 2.7 (m, 2H), 2.46 (dd, 1H, J₁=6.4 Hz, J₂=12.7 Hz), 2.31 (dd, 1H,J₁=6.8 Hz, J₂=12.4 Hz), 1.90 (m, 3H), 1.41 (s, 3H), 1.32 (m, 1H), 0.89(m, 1H), 0.82 (d, 3H, J=7.2 Hz), 0.50 (m, 2H), 0.11 (m, 2H). MS (ESI)m/z 481, 483 (M+H)+; Anal. Calcd. for C₂₇H₃₃N₂OBr.0.1H₂O: C, 67.10; H,6.92; N, 5.80. Found: C, 67.00; H, 6.94; N, 5.72.

(±)-3-(Cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-N-(2-bromophenethyl)-2,6-methano-3-benzazocine-8-carboxamide(31). Prepared using Method A and 2-(2-bromophenyl)ethanamine. Off-whitefoam (150 mg, 56%). ¹H NMR (300 MHz, CDCl₃) δ 7.64 (s, 1H), 7.58 (d, 1H,J=7.8 Hz), 7.40 (d, 1H), 7.28 (m, 2H), 7.1 (m, 2H), 6.16 (t, 1H, J=6Hz), 3.73 (q, 2H, J=6.6 Hz), 3.15 (m, 1H), 3.11 (t, 2H, J=7.0 Hz), 2.95(d, 1H, J=19 Hz), 2.7 (m, 2H), 2.46 (dd, 1H, J₁=6.4 Hz, J₂=12.7 Hz),2.31 (dd, 1H, J₁=6.8 Hz, J₂=12.4 Hz), 1.90 (m, 3H), 1.42 (s, 3H), 1.32(m, 1H), 0.89 (m, 1H), 0.83 (d, 3H, J=7.2 Hz), 0.51 (m, 2H), 0.11 (m,2H). MS (ESI) m/z 481, 483 (M+H)+; Anal. Calcd. for C₂₇H₃₃N₂OBr: C,67.35; H, 6.91; N, 5.82. Found: C, 67.22; H, 6.91; N, 5.78.

(±)-3-(Cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-N-(4-phenoxyphenethyl)-2,6-methano-3-benzazocine-8-carboxamide(33). Prepared using Method A and 2-(4-phenoxyphenyl)ethanamine.Off-white foam (145 mg, 67%). ¹H NMR (500 MHz, CDCl₃) δ 7.63 (s, 1H),7.37 (d, 1H, J=8 Hz), 7.33 (t, 2H, J=8 Hz), 7.20 (d, 2H, J=8.5 Hz), 7.09(m, 2H), 6.99 (d, 2H, J=8 Hz), 6.96 (d, 2H, J=8 Hz), 6.16 (t, 1H, J=6Hz), 3.68 (q, 2H, J=6.5 Hz), 3.14 (m, 1H), 2.94 (d, 1H, J=20 Hz), 2.91(t, 2H, J=6.9 Hz), 2.69 (m, 2H), 2.46 (dd, 1H, J₁=6.5 Hz, J₂=12.5 Hz),2.31 (dd, 1H, J₁=6.5 Hz, J₂=12.5 Hz), 1.90 (m, 3H), 1.40 (s, 3H), 1.31(d, 1H, J=10 Hz), 0.86 (m, 1H), 0.82 (d, 3H, J=7.0 Hz), 0.50 (d, 2H,J=8.0 Hz), 0.10 (m, 2H). MS (ESI) m/z 495 (M+H)+; Anal. Calcd. forC₃₃H₃₈N₂O₂.0.25H₂O: C, 79.40; H, 7.77; N, 5.61. Found: C, 79.37; H,7.89; N, 5.77.

(±)-3-(Cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-N-(3-phenoxyphenethyl)-2,6-methano-3-benzazocine-8-carboxamide(34). Prepared using Method A and 2-(3-phenoxyphenyl)ethanamine.Off-white foam (124 mg, 63%). ¹H NMR (500 MHz, CDCl₃) δ 7.63 (s, 1H),7.35 (d, 1H, J=8 Hz), 7.29 (m, 3H), 7.09 (m, 2H), 6.98 (m, 3H), 6.88 (m,2H), 6.15 (t, 1H, J=6 Hz), 3.68 (q, 2H, J=6.5 Hz), 3.14 (m, 1H), 2.94(d, 1H, J=21.5 Hz), 2.89 (t, 2H, J=7.0 Hz), 2.69 (m, 2H), 2.46 (dd, 1H,J₁=6.3 Hz, J₂=12.8 Hz), 2.31 (dd, 1H, J₁=6.5 Hz, J₂=12.5 Hz), 1.90 (m,3H), 1.40 (s, 3H), 1.32 (d, 1H, J=10 Hz), 0.85 (m, 1H), 0.82 (d, 3H,J=7.0 Hz), 0.51 (d, 2H, J=8.0 Hz), 0.10 (m, 2H). MS (ESI) m/z 495(M+H)+; Anal. Calcd. for C₃₃H₃₈N₂O₂.0.2H₂O: C, 79.55; H, 7.77; N, 5.62.Found: C, 79.65; H, 7.83; N, 5.53.

(±)-3-(Cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-N-(2-phenoxyphenethyl)-2,6-methano-3-benzazocine-8-carboxamide(35). Prepared using Method A and 2-(2-phenoxyphenyl)ethanamine.Off-white foam (152 mg, 65%). ¹H NMR (300 MHz, CDCl₃) δ 7.65 (s, 1H),7.40 (d, 1H, J=7.8 Hz), 7.3 (m, 3H), 7.2 (m, 1H), 7.08 (m, 3H), 6.91 (m,3H), 6.36 (t, 1H, J=6 Hz), 3.71 (q, 2H, J=6.3 Hz), 3.14 (m, 1H), 2.97(t, 2H, J=6.75 Hz), 2.95 (d, 1H, J=18.9 Hz), 2.7 (m, 2H), 2.46 (dd, 1H,J₁=6.2 Hz, J₂=12.8 Hz), 2.31 (dd, 1H, J₁=6.6 Hz, J₂=12.9 Hz), 1.90 (m,3H), 1.40 (s, 3H), 1.32 (m, 1H), 0.86 (m, 1H), 0.82 (d, 3H, J=7.2 Hz),0.51 (d, 2H, J=8.1 Hz), 0.11 (m, 2H). MS (ESI) m/z 495 (M+H)+; Anal.Calcd. for C₃₃H₃₈N₂O₂.0.2H₂O: C, 79.55; H, 7.77; N, 5.62. Found: C,79.54; H, 7.86; N, 5.69.

(±)-3-(Cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-N-(2-(naphthalen-2-yl)ethyl)-2,6-methano-3-benzazocine-8-carboxamide(37). Prepared using Method A and 2-(naphthalen-2-yl)ethanamine.Off-white foam (93 mg, 55%). ¹H NMR (300 MHz, CDCl₃) δ 7.77 (m, 3H),7.65 (s, 2H), 7.3-7.5 (m, 4H), 7.04 (d, 1H, J=7.8 Hz), 6.5 (t, 1H, J=6Hz), 3.75 (q, 2H, J=6.4 Hz), 3.1 (m, 3H), 2.9 (d, 1H, J=19 Hz), 2.65 (m,2H), 2.45 (dd, 1H, J₁=6.5 Hz, J₂=12.5 Hz), 2.30 (dd, 1H, J₁=6.6 Hz,J₂=12.9 Hz), 1.90 (m, 3H), 1.33 (s, 3H), 1.30 (d, 1H, J=11.1 Hz), 0.85(m, 1H), 0.79 (d, 3H, J=7.2 Hz), 0.51 (d, 2H, J=6.6 Hz), 0.10 (m, 2H).MS (ESI) m/z 453 (M+H)+; Anal. Calcd. for C₃₁H₃₆N₂O.1.0H₂O: C, 79.11; H,8.14; N, 5.95. Found: C, 79.31; H, 7.83; N, 5.92.

(±)-3-(Cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-N-(3-(naphthalen-2-yl)propyl)-2,6-methano-3-benzazocine-8-carboxamide(38). Prepared using Method A and 3-(naphthalen-2-yl)propan-1-amine.Off-white foam (85 mg, 56%). ¹H NMR (300 MHz, CDCl₃) δ 7.8 (m, 3H), 7.66(s, 2H), 7.4-7.5 (m, 2H), 7.37 (d, 1H, J=8.3 Hz), 7.26 (m, 1H), 7.03 (d,1H, J=7.8 Hz), 6.08 (t, 1H, J=6 Hz), 3.54 (q, 2H, J=6.5 Hz), 3.15 (m,1H), 2.94 (d, 1H, J=20 Hz), 2.91 (t, 2H, J=7.5 Hz), 2.65 (m, 2H), 2.44(dd, 1H, J₁=6.5 Hz, J₂=12.5 Hz), 2.31 (dd, 1H, J₁=6.6 Hz, J₂=12.9 Hz),2.07 (m, 2H), 1.90 (m, 3H), 1.41 (s, 3H), 1.34 (m, 1H), 0.87 (m, 1H),0.82 (d, 3H, J=7 Hz), 0.52 (m, 2H), 0.11 (m, 2H). MS (ESI) m/z 467(M+H)+; Anal. Calcd. for C₃₂H₃₈N₂O.0.3H₂O: C, 81.42; H, 8.24; N, 5.93.Found: C, 81.33; H, 8.19; N, 5.89.

(±)-3-(Cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-N-(2-(naphthalen-1-yl)ethyl)-2,6-methano-3-benzazocine-8-carboxamide(40). Prepared using Method A and 2-(naphthalen-1-yl)ethanamine.Off-white foam (77.5 mg, 24%). ¹H NMR (300 MHz, CDCl₃) δ 8.19 (d, 1H,J=8.1 Hz), 7.89 (d, 1H, J=7.8 Hz), 7.78 (d, 1H, J=7.8 Hz), 7.3-7.6 (m,6H), 7.08 (d, 1H, J=8 Hz), 6.16 (t, 1H, J=6 Hz), 3.83 (q, 2H, J=6.5 Hz),3.44 (t, 2H, J=7 Hz), 3.19 (s, 1H), 2.95 (d, 1H, J=19 Hz), 2.7 (m, 2H),2.49 (dd, 1H, J₁=6.4 Hz, J₂=12.7 Hz), 2.35 (dd, 1H, J₁=6.8 Hz, J₂=12.4Hz), 1.90 (m, 3H), 1.38 (s, 3H), 1.35 (m, 1H), 0.9 (m, 1H), 0.82 (d, 3H,J=7.2 Hz), 0.53 (m, 2H), 0.13 (m, 2H). MS (ESI) m/z 453 (M+H)+; Anal.Calcd. for C₃₁H₃₆N₂O.0.4H₂O: C, 80.97; H, 8.07; N, 6.09. Found: C,81.00; H, 7.98; N, 6.03.

(±)-3-(Cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-N-(3-(naphthalen-2-yl)propyl)-2,6-methano-3-benzazocine-8-carboxamide(41). Prepared using Method A and 3-(naphthalen-2-yl)propan-1-amine.White foam (60 mg, 41%). ¹H NMR (300 MHz, CDCl₃) δ 8.04 (d, 1H, J=8 Hz),7.86 (d, 1H, J=7.3 Hz), 7.73 (d, 1H, J=7.6 Hz), 7.65 (s, 1H), 7.3 (m,5H), 7.08 (d, 1H, J=8 Hz), 6.05 (t, 1H, J=6 Hz), 3.57 (q, 2H, J=6.8 Hz),3.19 (t, 2H, J=7.7 Hz), 3.15 (m, 1H), 2.95 (d, 1H, J=19 Hz), 2.65 (m,2H), 2.46 (dd, 1H, J₁=6.5 Hz, J₂=12.6 Hz), 2.31 (dd, 1H, J₁=6.6 Hz,J₂=12.4 Hz), 2.11 (m, 2H), 1.90 (m, 3H), 1.41 (s, 3H), 1.37 (d, 1H,J=11.5 Hz), 0.87 (m, 1H), 0.82 (d, 3H, J=7 Hz), 0.50 (m, 2H), 0.11 (m,2H). MS (ESI) m/z 467 (M+H)+; Anal. Calcd. for C₃₂H₃₈N₂O.0.5H₂O: C,80.80; H, 8.26; N, 5.89. Found: C, 80.90; H, 8.09; N, 5.87.

(−)-Q-naltrexone (71). Prepared using Scheme 2 and2-(biphenyl-4-yl)ethanamine. White foam (160 mg, 61%). ¹H NMR (500 MHz,CDCl₃) δ 7.82 (d, 1H, J=7.8 Hz), 7.73 (t, 1H, J=5.6 Hz), 7.58 (d, 2H,J=7.0 Hz), 7.54 (d, 2H, J=8.3 Hz), 7.42 (m, 4H), 7.33 (t, 1H, J=7.5 Hz),6.81 (d, 1H, J=8.1 Hz), 5.2 (bs, 1H), 4.75 (s, 1H), 3.81 (m, 1H), 3.73(m, 1H), 3.22 (d, 1H, J=5.9 Hz), 3.12 (d, 1H, J=19.1 Hz), 3.05 (m, 3H),2.71 (dd, 1H, J₁=12.2 Hz, J₂=4.6 Hz), 2.63 (dd, 1H, J₁=9.1 Hz, J₂=6.0Hz), 2.44 (dt, 1H, J₁=5.2 Hz, J₂=12.5 Hz), 2.41 (d, 2H, J=6.3 Hz), 2.32(td, 1H, J₁=3.0 Hz, J₂=14.4 Hz), 2.08 (dt, 1H, J₁=3.6 Hz, J₂=12.2 Hz),1.92 (m, 1H), 1.58 (dt, 1H, J₁=3.4 Hz, J₂=14.0 Hz), 1.50 (dd, 1H, J₁=2.5Hz, J₂=12.9 Hz), 0.87 (m, 1H), 0.57 (m, 2H), 0.15 (m, 2H). MS (ESI) m/z549 (M+H)+; Anal. Calcd. for C₃₅H₃₆N₂O₄.0.75H₂O: C, 74.78; H, 6.67; N,4.89. Found: C, 74.71; H, 6.67; N, 4.95. [α]²⁵D=-108.6° (c=0.75,acetone).

(−)-Q-buprenorphine (75). Prepared using Scheme 2 and2-(biphenyl-4-yl)ethanamine. White foam (150 mg, 73%). ¹H NMR (500 MHz,CDCl₃) δ 7.87 (d, 1H, J=7.8 Hz), 7.56 (d, 2H, J=7.1 Hz), 7.52 (d, 2H,J=8.0 Hz), 7.44 (t, 2H, J=7.6 Hz), 7.37 (t, 1H, J=5.6 Hz), 7.33 (t, 1H,J=7.5 Hz), 7.26 (d, 2H, J=7.8 Hz), 6.74 (d, 1H, J=8.0 Hz), 5.64 (s, 1H),4.47 (s, 1H), 3.74 (q, 2H, J=6.6 Hz), 3.22 (s, 3H), 2.85-3.1 (m, 5H),2.63 (dd, 1H, J₁=5.0 Hz, J₂=11.9 Hz), 2.2-2.4 (m, 4H), 2.12 (t, 1H,J=9.8 Hz), 1.97 (dt, 1H, J₁=5.6 Hz, J₂=13.0 Hz), 1.80 (t, 1H, J=12.8),1.61 (m, 2H), 1.32 (s, 3H), 1.29 (m, 1H), 1.06 (m 1H), 1.03 (s, 9H),0.80 (m, 1H), 0.63 (m, 1H), 0.49 (m, 2H), 0.12 (m, 2H). MS (ESI) m/z 675(M+H)+; Anal. Calcd. for C₄₄H₅₄N₂O₄.0.25H₂O: C, 77.78; H, 8.09; N, 4.12.Found: C, 77.64; H, 8.03; N, 4.05. [α]²⁵D=−68.3° (c=0.75, acetone).

(−)-Q-nalbuphine (77). Prepared using Scheme 2 and2-(biphenyl-4-yl)ethanamine. White foam (170 mg, 59%). ¹H NMR (500 MHz,CDCl₃) δ 7.85 (d, 1H, J=8.0 Hz), 7.57 (d, 2H, J=7.3 Hz), 7.53 (d, 2H,J=8.1 Hz), 7.54 (t, 1H, J=5.6 Hz), 7.42 (t, 2H, J=7.2 Hz), 7.33 (t, 1H,J=7.3 Hz), 7.30 (d, 2H, J=8.0 Hz), 6.75 (d, 1H, J=8.1 Hz), 4.9 (bs, 1H),4.65 (s, 1H), 4.16 (bs, 1H), 3.81 (m, 1H), 3.63 (m, 1H), 3.12 (d, 1H,J=19.1 Hz), 3.00 (m, 1H), 2.95 (m, 1H), 2.81 (d, 1H, J=5.9 Hz), 2.65(dd, 1H, J₁=19.0 Hz, J₂=6.3 Hz), 2.47 (m, 4H), 2.17 (m, 2H), 2.06 (m,2H), 1.91 (m, 1H), 1.86 (m, 1H), 1.55-1.75 (m, 4H), 1.40 (m, 2H), 1.06(m, 1H). MS (ESI) m/z 565 (M+H)+; Anal. Calcd. for C₃₆H₄₀N₂O₄.0.0H₂O: C,76.57; H, 7.14; N, 4.96. Found: C, 76.54; H, 7.22; N, 4.92.[α]²⁵D=−109.3° (c=0.75, acetone).

(−)-Q-butorphanol (79). Prepared using Scheme 2 and2-(biphenyl-4-yl)ethanamine. White foam (75 mg, 81%). ¹H NMR (500 MHz,CDCl₃) δ 7.69 (S, 1H), 7.57 (d, 2H, J=7.0 Hz), 7.54 (d, 2H, J=8.0 Hz),7.44 (d, 1H, J=7.3 Hz), 7.43 (t, 2H, J=7.8 Hz), 7.33 (t, 1H, J=7.3 Hz),7.30 (d, 2H, J=8.0 Hz), 7.11 (d, 1H, J=7.8 Hz), 6.4 (bs, 1H), 4.6 (bs,1H), 3.72 (m, 2H), 3.10 (d, 1H, J=18.8 Hz), 2.96 (t, 2H, J=7.1 Hz), 2.81(dd, 1H, J₁=6.2 Hz, J₂=19 Hz), 2.64 (d, 1H, J=6.1 Hz), 2.45 (m, 3H),2.34 (m, 1H), 1.75-2.10 (m, 9H), 1.65 (m, 2H), 1.50 (m, 1H), 1.2-1.45(m, 4H), 0.97 (m, 1H). MS (ESI) m/z 535 (M+H)+; Anal. Calcd. forC₃₆H₄₂N₂O₂. 0.33H₂O: C, 79.97; H, 7.95; N, 5.18. Found: C, 79.92; H,8.03; N, 5.19. [α]²⁵D=−54.8° (c=0.75, acetone).

Q-naltrexone ring opened (81). Prepared using the method described inpublished US application 2006/0111384, which derives from Coop et al.,“δ Opioid Affinity and Selectivity of4-Hydroxy-3-methoxyindolomorphianan Analogues Related to Naltrindole”,J. Med. Chem. 1999, 42, 1673. Zinc dust (65 mg, 3.75 mmol) was added inportions over 20 min to a solution of (−)-71 Q-naltrexone (103 mg, 0.19mmol), in HCl (37%, 0.2 mL) and AcOH (5 mL) at reflux. After heating atreflux for a further 10 min, the reaction was cooled by the addition ofice/water (50 mL) and basified (pH 9) with NH₄OH, and the products wereextracted into CH₂C₁₂ (3×50 mL). The organic extracts were washed withbrine (100 mL), dried, concentrated, and purified by columnchromatography (SiO₂, CH₂C₁₂:CH₃OH:NH₄OH 25:1:0.1) to give 81 (71.7 mg,70%): ¹H NMR (300 MHz, CDCl₃) δ 13.33 (s, 1H), 7.59 (d, 2H, J=7.8 Hz),7.57 (d, 2H, J=8.1 Hz), 7.45 (t, 2H, J=7.4 Hz), 7.36 (t, 1H, J=7.5 Hz),7.32 (d, 2H. J=8.1 Hz), 6.93 (d, 1H, J=8.1 Hz), 6.44 (d, 1H, J=8.4 Hz),6.38 (bt, 1H), 4.70 (bs, 1H), 4.10 (d, 1H, J=13.5 Hz), 3.70 (m, 2H),3.11 (d, 1H, J=6.0 Hz), 2.9-3.0 (m, 4H), 2.76-2.87 (m, 2H), 2.63 (m,1H), 2.35 (d, 2H, J=6.5 Hz), 1.5-2.2 (m, 8H), 0.87 (m, 1H), 0.59 (m,2H), 0.11 (m, 2H). MS (ESI) m/z 551 (M+H)+; Anal. Calcd. forC₃₅H₃₈N₂O₄.0.3H₂O: C, 75.60; H, 7.00; N, 5.04. Found: C, 75.56; H, 6.90;N, 4.87.

In general, the chemistry described above works in the presence of thevariety of functional groups found on known core structures. Theexceptions would be morphine and congeners having a free 6-OH, which canbe protected by a TBDPS (t-butyldiphenylsilyl) group [see Wentland etal., “Selective Protection and Functionalization of Morphine . . . ”, J.Med. Chem. 43, 3558-3565 (2000)].

I claim:
 1. A compound of formula:

wherein Q is

A is (CH₂)_(n), wherein one or more CH₂ may be replaced by —O—, cycloalkyl or CR^(1a)R^(1b); R^(1a) and R^(1b) are chosen independently from hydrogen, halogen, lower alkyl, lower alkoxy and lower alkylthio;

is an aryl or heteroaryl residue of one to three rings; R¹⁰ is one or two residues chosen independently from hydrogen, hydroxyl, halogen, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, halo(C₁-C₆)alkyl and halo(C₁-C₆)alkoxy and (C₁-C₆)alkylthio; R¹¹ is H or

is an aryl or heteroaryl residue of one to three rings; A′ is (CH₂)_(m) wherein one or more CH₂ may be replaced by —O—, cycloalkyl, —CR^(1a)R^(1b), —C(═O)— or —NH—; R¹² is chosen from hydrogen and lower alkyl; R¹⁵ is one or two residues chosen independently from hydrogen, hydroxyl, halogen, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, halo(C₁-C₆)alkyl and halo(C₁-C₆)alkoxy and (C₁-C₆)alkylthio; m is zero or an integer from 1 to 6; and n is an integer from 1 to
 6. 2. A method of treating a patient suffering from a disease or condition wherein said disease or condition is chosen from the group consisting of pain, pruritis, diarrhea, irritable bowel syndrome, gastrointestinal motility disorder, obesity, respiratory depression, convulsions, coughing, hyperalgesia, dyskinesia and drug addiction comprising administering to said patient a compound of claim 1 or a pharmaceutically acceptable salt thereof. 